Prevention of Type 2 Diabetes: Evidence and Strategies

The international DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medications) trial randomly assigned more than 5000 participants with IFG and/or IGT to rosiglitazone, ramipril, or placebo in a 2 × 2 factorial design [46]. In participants receiving rosiglitazone, the risk for progression to diabetes was reduced by 60% and the likelihood of regression to normoglycemia was increased by 71% when compared to placebo. However, the use of rosiglitazone was associated with an increased risk of new-onset congestive heart failure and a mean weight gain of 2.2 kg, thought to reflect increased subcutaneous gluteal fat deposition, with an observed decreased waist-to-hip ratio.

Interestingly, in a passive follow-up of the DREAM study conducted a median 1.6 years after the end of the trial and 4.3 years after randomization, participants treated with rosiglitazone had a 39% lower incidence of diabetes compared to placebo participants, and 17% more of them regressed from prediabetes to normoglycemia [47]. Nonetheless, there was no difference between the 2 groups when the analysis was restricted to the passive follow-up period, suggesting a time-limited exposure to rosiglitazone reduces the longer-term incidence of diabetes by likely delaying but not reversing the underlying disease process.

The third large trial assessing the efficacy of a TZD in preventing diabetes was the Actos Now for the prevention of diabetes (ACT NOW) trial, which was a randomized, double-blinded study that assigned 602 patients with IGT to pioglitazone 45 mg daily or placebo [48]. Over a median follow-up of 2.6 years, pioglitazone was associated with a 72% lower annual rate of progression to diabetes (2.1% compared to 7.6 % in placebo group), and a higher rate of conversion to normal glucose tolerance (48%). In addition, pioglitazone had favorable effects on fasting and 2-hour blood glucose, A1C level, diastolic blood pressure, carotid intima thickness, and HDL cholesterol. As in the DREAM trial, an increased incidence of edema and weight gain was observed with pioglitazone.

Unlike the strong evidence supporting TZDs as an approach to diabetes prevention in the US trials, the Indian Diabetes Prevention Program-2 (IDPP-2) trial, which randomized 497 participants with IGT to lifestyle modifications with pioglitazone versus lifestyle modifications with placebo, did not demonstrate a significant reduction in diabetes at 3 years’ follow-up, suggesting a possible ethnicity-related variation in the effect of the medication [49]. In 2011, the French and German medications regulatory agency withdrew pioglitazone from the market because of a potential increase in incidence of bladder cancer with the cumulative use of more than 28 g of pioglitazone. In the United States, the Food and Drug Administration is performing an extensive review of data and advises against the use of pioglitazone in patients with a history of bladder cancer.

In summary, TZDs demonstrated significant efficacy in preventing diabetes in many patients at risk, but their safety concerns, particularly the associated new onset of congestive heart failure and potential increased risk of bladder cancer, might outweigh this benefit.

Combination Metformin and Thiazolidinediones

As metformin and rosiglitazone both have preventive benefits in diabetes, and rosiglitazone is associated with numerous side effects at a higher dose, a combination of metformin and low-dose rosiglitazone was evaluated in in the CAnadian Normoglycemia Outcomes Evaluation (CANOE) trial [50]. A total of 207 patients with IGT were randomly assigned to receive combination metformin (500 mg twice daily) and rosiglitazone (2 mg daily) versus placebo for a median of 3.9 years. The combination therapy was associated with a 66% relative risk reduction of progression to diabetes.